Eric Chen has developed a computer simulation to speed up discovery of new influenza drugs
WASHINGTON — Eric Chen, 17, wants to make sure that fewer people have to suffer through the flu. The senior at Canyon Crest Academy in San Diego, Calif., has developed a new computer program to help. His program turned up six candidate compounds that might stop the influenza virus dead in its tracks. This week, Eric described the drugs — and how he found them — at the 2014 Intel Science Talent Search.
This yearly competition in Washington, D.C., run by Society for Science & the Public, brings together 40 of the brightest high school seniors from all over the country to share their research findings.
Most flu sufferers experience fever, chills, headaches, sore throats, a stuffy nose or other annoying symptoms. But the disease can be especially dangerous — even deadly — in the very young, the very old or anyone with a weak immune system.
Getting a yearly vaccination can protect us against the more common types of flu. But many people do not get the shot. And the annual vaccine doesn’t cover some of the less common types of flu virus. Eric wanted to tackle the disease differently.
Vaccines train the immune system to recognize the proteins coating the outside of the flu germ. Once the body recognizes the flu, it can mount an immune response to get rid of it. But the virus mutates, changing its protein coat very quickly. This means that vaccines designed to recognize the outside of a flu germ have to be changed every year to match the protein coat worn by the bug. If it doesn’t match the new protein, the vaccine simply won’t recognize the virus — or work.
Eric decided to avoid this problem entirely. His drug candidates scout for a protein that the virus uses for replication. It’s an internal enzyme called endonuclease. It cuts through DNA, the molecule that carries all the information needed to run a cell. It also slices through RNA, the molecule that carries information from DNA to make proteins. The action of this enzyme is vital to making sure that genetic information is copied and transmitted correctly as each new cell develops. Indeed, the influenza virus relies on this enzyme to reproduce and spread. If Eric could find a drug that blocked the enzyme, he might shut the flu bug down.
To find chemicals that might target endonuclease, Eric turned to Chembridge. This company, based in San Diego, Calif., has a library of thousands of chemical compounds. Eric invented a computer program that could select molecules based on certain characteristics. He screened 450,000 chemicals, looking for traits that would make a drug hard to get into the body or too large to interact with the virus. “If the chemical is too complex,” he explains, “or if it can’t dissolve in water, it’s not going to be a good drug.”
With this first screen, he was able to filter out 350,000 candidate chemicals.
Eric then developed a second computer program. This one modeled how a drug might interact with the endonuclease. Instead of screening for what wouldn’t work, he screened the remaining 100,000 chemicals for ones that might shut down endonuclease. The ideal drug would fit into the endonuclease molecule like a key fits into a lock. Indeed, it would take the place of the DNA and RNA that the enzyme usually snips.
One by one, the new program attempted to “fit” each chemical into the endonuclease. Afterward, it ranked each chemical on how well it fit into the enzyme. When this model finished, he was whittled down the candidate drugs to 237.
The teen then tested each one, putting it into a solution with endonuclease, DNA and RNA. Since endonuclease slices DNA and RNA, he looked for drugs that could prevent the enzyme from doing its job. Out of all the compounds, six appeared to be endonuclease inhibitors. If they work in the body the way they worked in his cell model, they might show promise in fighting flu. Eric is now in talks with drug companies about developing some of these drugs so they might be tested in humans.
Endonuclease is a good target for a flu medicine because it doesn’t change as fast as the outer coating of the virus. This means that a drug that blocks endonuclease might work against any strain of flu — and for many years.
Eric notes that his work is not over. He still has to make sure the drugs will won’t sicken people. “Humans have a lot of endonucleases,” he says. “So something that inhibits the flu endonuclease might inhibit a human endonuclease.” But the teen is not too worried. The human and viral enzymes have many differences. So he hopes that at least one of his new candidate drugs will leave the human enzyme alone.
Any candidate drug will have to go through many years of testing to make sure it is effective and safe in people. Even if it passes these hurdles, it still could be another 10 years or more before a doctor is able to prescribe it. But any drug that does make it could one day reduce a lot of misery — and possibly save lives.
DNA (short for deoxyribonucleic acid) A long, spiral-shaped molecule inside most living cells that carries genetic instructions. In all living things, from plants and animals to microbes, these instructions tell cells which molecules to make.
enzyme Molecules made by living things to speed up chemical reactions.
endonucleases Enzymes that cut sequences of DNA and RNA. They are important for DNA copying (replication). For instance, these enzymes will cut DNA at specific sites to ensure that any mistakes made when DNA is copied will be corrected.
influenza (or flu) A highly contagious viral infection of the respiratory passages causing fever and severe aching. It often occurs as an epidemic.
RNA A molecule that helps “read” the genetic information contained in DNA. A cell’s molecular machinery reads DNA to create RNA, and then reads RNA to create proteins.
strain (as in microbial) Organisms that belong to the same species that share some small but definable characteristics. For example, biologists breed certain strains of mice that may have a particular susceptibility to disease. Certain bacteria may develop one or more mutations that turn them into a strain that is immune to the ordinarily lethal effect of one or more drugs.
virus Tiny infectious agents consisting of RNA or DNA surrounded by protein. Viruses can reproduce only by injecting their genetic material into the cells of living creatures. Although scientists frequently refer to viruses as live or dead, in fact no virus is truly alive. It doesn’t eat like animals do, or make its own food the way plants do. It must hijack the cellular machinery of a living cell in order to survive.